Cyclohexyl-linked tricyclic isoxazoles are potent and selective modulators of the multidrug resistance protein (MRP1).
Bioorg Med Chem Lett
; 15(24): 5526-30, 2005 Dec 15.
Article
em En
| MEDLINE
| ID: mdl-16202586
ABSTRACT
Structure-activity relationship (SAR) studies on the tricyclic isoxazole series of MRP1 modulators have resulted in the identification of potent and selective inhibitors containing cyclohexyl-based linkers. These studies ultimately identified compound 21b, which reverses drug resistance to MRP1 substrates, such as doxorubicin, in HeLa-T5 cells (EC(50)=0.093microM), while showing no inherent cytotoxicity. Additionally, 21b inhibits ATP-dependent, MRP1-mediated LTC(4) uptake into membrane vesicles prepared from the MRP1-overexpressing HeLa-T5 cells (EC(50)=0.064microM) and shows selectivity (1115-fold) against the related transporter, P-glycoprotein, in HL60/Adr and HL60/Vinc cells. Finally, when dosed in combination with the oncolytic MRP1 substrate vincristine, 21b showed tumor regression and growth delay in MRP1-overexpressing tumors in vivo.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas Associadas à Resistência a Múltiplos Medicamentos
/
Isoxazóis
Limite:
Humans
Idioma:
En
Ano de publicação:
2005
Tipo de documento:
Article